Download Krypton-enhanced ventilation CT with dual-energy

Original Research
Krypton-enhanced ventilation CT with dual-energy technique: Experimental
study for proper krypton concentration
Yong Eun Chung ([email protected])1, Sae Rom Hong ([email protected])1, Mi-Jung Lee
([email protected])1,
Myungsu
Lee
([email protected])1,
Young
Jin
Kim
([email protected])1, Jin Hur ([email protected])1, Yoo Jin Hong ([email protected])1, Byoung
Wook Choi ([email protected])1, Hye-Jeong Lee ([email protected])1*
1
Department of Radiology, Research Institute of Radiological Science, Severance Hospital,
Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea
*
Corresponding author: Hye-Jeong Lee
Department of Radiology, Research Institute of Radiological Science, Severance Hospital,
Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea
Tel: 82-2-2228-7400, Fax: 82-2-393-3035
E-mail: [email protected]
1
ABSTRACT
Backgraound
To assess the feasibility of krypton-enhanced ventilation CT using dual energy (DE)
technique for each krypton concentration and to determine the appropriate krypton
concentration for DE ventilation CT through an animal study.
Methods
Baseline DECT was first performed on seven New Zealand white rabbits. The animals were
then ventilated using 20%, 30%, 40%, 50%, 60% to 70% krypton concentration, and DECT
was performed for each concentration. Krypton extraction was performed through a
workstation, and results were displayed on a color map. Overlay values were obtained by two
observers in consensus readings. A linear mixed model was used to correlate overlay HU
values and krypton concentrations. Visual assessments of the homogeneity of krypton maps
were also performed.
Results
Mean overlay HU values according to krypton concentration were as follows; 20% krypton,
1.68±5.15; 30% krypton, 3.73±5.93; 40% krypton, 6.92±5.51; 50% krypton, 10.88±5.17;
60% krypton, 14.54±4.23; and 70% krypton, 18.79±3.63. We observed a significant
correlation between overlay HU values on krypton maps and krypton concentrations
(P<0.001). For the krypton color maps, all observers determined homogenous enhancement
on the 70% krypton map for all animals.
Conclusions
It is feasible to evaluate lung ventilation function using DECT with krypton concentration of
at least 70%.
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Key Words
Lung function, Ventilation, Krypton, Dual Energy CT, Material decomposition
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Background
Multidetector computed tomography (MDCT) provides high-resolution morphological
information and is the first-line choice for evaluating lung disease; however, the evaluation of
regional lung ventilation function is also important for localizing pathologic areas of the
lungs. Several previous studies have shown that xenon inhalation CT can be used to depict
lung ventilation due to its radio-opaque character [1-3]. MDCT also has the potential to
assess pulmonary function; however, variability in baseline lung attenuation between images
due to misregistration artifacts and different respiration levels, in spite of xenon inhalation,
hamper the accurate measurement of lung ventilation function [4].
Dual source CT utilizes two orthogonally-mounted detectors and tube arrays operating
simultaneously that are set to different tube potentials. It has recently been used for dual
energy CT (DECT) acquisition with minimal misregistration artifacts [5,6] and maps of
xenon can be extracted from the resultant datasets using dedicated software. Several studies
have shown that it is technically feasible to use DECT in dynamic and static evaluations of
regional ventilation with ventilation maps, and thin-section CT lung images can be
simultaneously generated [4,7-11]; however, the use of xenon is limited by its high cost, in
addition to adverse effects such as respiratory depression, somnolence, headache, nausea,
lightheadedness, and labile emotion.
Inert krypton gas (atomic number 36) is less radio-opaque than xenon (atomic number 54),
but it is nevertheless perceptibly radio-opaque with general radiographic techniques in
comparison to air [12]. As an inhalation contrast medium, it has the advantage of being much
less soluble in tissue, and therefore it does not produce the anesthetic effects seen with xenon
[13]. Moreover, krypton is also relatively inexpensive, with a cost that is about one sixth that
of xenon. We assumed that krypton is radio-opaque enough to allow extraction and
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quantification based on DECT; however, to our knowledge, there have only been a few
reports about krypton-enhanced ventilation CT [14]. Therefore, the purpose of this study was
to assess the feasibility of krypton-enhanced ventilation CT using the dual energy technique
for each krypton concentration and to determine the appropriate krypton mixture
concentration for the ventilation CT through an animal study.
Methods
Animal preparation
The study protocol was approved by our institutional animal experimental committee and
performed according to local animal care guidelines. Seven New Zealand white rabbits with
an average body weight of 3.0 kg were used in this study. Anesthesia was induced with an
intramuscular injection of tiletamine (30 mg/kg, Zoletil; Virbac Laboratories, Carros, France)
and xylazine (10 mg/kg, Rompun; Bayer AG, Levenkusen, Germany).
After anesthesia, animals were intubated with a polyethylene tube 3.0 mm in diameter
(Mallinckordt, Athlone, Ireland) and ventilated using a mechanical ventilator (Royal-77S;
Royal Medical, Seoul, Korea). Deep anesthesia was maintained using isoflurane (Forane;
Abbott Laboratories, North Chicago, IL, USA) through a ventilator without spontaneous
respiration. The tidal volume was 20 mL, the respiratory rate was 20 breaths per minute, and
the inspiration-expiration ratio was 1:2 during the experiment. During CT scans, the
respiratory rate was 5 breaths per minute, and the inspiration-expiration ratio was 2:1.
Because krypton replaced nitrogen, the animals were ventilated with oxygen and krypton.
Oxygen saturation was monitored throughout the study.
Imaging protocols
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All CT scans were performed using a second-generation dual source dual energy CT
(Somatom Definition FLASH; Siemens Medical Solutions, Forchheim, Germany). The
rabbits were placed centrally in the scanner to ensure that the entire thorax was covered by
the field-of-view of both the larger and smaller tube detector arrays.
First, baseline DECT of the chest was performed to exclude any pulmonary lesions and to
obtain a baseline HU of the lung parenchyma in the 7 rabbits. Next, animals were ventilated
using 20% krypton (a mixture of 20% krypton and 80% oxygen) for 3 minutes. A single scan
with a dual energy technique that covered the entire thorax was performed at the end of
krypton inhalation. The concentration of krypton was increased from 20% to 70% by steps of
10%, and a total of 6 sessions of DECT were performed. The maximum concentration of
krypton was set to 70% because the atmosphere contains approximately 21% oxygen, and a
lower concentration of oxygen during ventilation could affect the oxygen saturation in the
blood [15]. The time interval between each session was 10 minutes. Between intervals, the
animals were ventilated with 100% oxygen.
The same parameters were used for baseline scanning and single scanning covering the
entire thorax during krypton inhalation. DECT protocol was as follows: tube voltage of
80kVp and 140kVp with tube currents of 213mAs and 62mAs, respectively. Detector
collimation 64 x 0.6mm, matrix 512 x 512, pitch 0.5, gantry rotation time 280ms, and scan
time was about 2-3s.
Image Reconstruction and Analysis
From the raw data of both detectors, images were automatically reconstructed into three
image datasets (conventional CT images): 80kVp, 140kVp, and weighted average 120kVp
images, which were fused images with 30% density information from the 80kVp image and
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70% from the 140kVp image. The images were reconstructed using a slice thickness of 0.6
mm, an increment interval of 0.6 mm, and a medium-smooth convolution kernel of D30f.
All CT images were transferred to an off-line workstation (Aquaris iNtuition V4.4.6,
TeraRecon, San Francisco, CA, USA). CT images were evaluated in consensus by two
radiologists (S.R.H and H.J.L with 1 and 6 years of experience in chest CT interpretation,
respectively) who were unaware of the krypton concentration. At first, the observers
examined for motion artifacts on the CT images and for morphological abnormality of the
lung parenchyma.
Next, three coronal images were produced to measure the CT number. Coronal images were
reformatted in accordance with the plane across the midline of the carina on axial images, 1cm anterior and posterior to the plane (Figure 1). Two observers placed circular regions of
interest (ROI) on both lungs for each coronal image. The size of the ROI was drawn as large
as possible while avoiding inclusion of the airways and vessels, and was kept constant for all
images of each animal. The CT number was measured at 80kVp, 140kVp, and weighted
average 120kVp for each krypton concentration. The difference in HU between the baseline
DECT and krypton-enhanced CT was calculated at weighted average 120kVp.
All images were also transferred to a commercially available workstation (Syngo MMWP
VE23A, Siemens Medical Solutions, Forchheim, Germany) for ventilation maps. Ventilation
maps using krypton were obtained at the workstation using a modified prototype of the
“Xenon” application class of the workstation, which was based on the material
decomposition method [6]. The material parameters were adjusted for krypton extraction as
follows: -995 HU for air at 80kVp; −1000 HU for air at 140kVp; 70 HU for soft tissue at
80kVp; 55 HU for soft tissue at 140kVp; -930 HU for krypton at 80kVp; -970 HU for
krypton at 140kVp; minimum value, −960 HU; maximum value, −500 HU; 4 for range;
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contrast media cutoff value of -50 HU. Pixels with densities outside of this range (below
−960 HU and above −500 HU) were set to 0 HU for krypton ventilation maps. We used “Hot
body 8 bit” to show krypton ventilation maps using fused images (50% of anatomical CT
images and 50% of ventilation images).
For the krypton ventilation maps, the overlay HU value, which is the DECT HU difference
caused by krypton inhalation, was obtained by the two observers in the normal lung using
ROIs of similar size at the corresponding locations on conventional CT images.
Visual assessment was also performed for krypton ventilation maps to show either the
homogeneity or heterogeneity of krypton distribution for the entire normal lungs. On krypton
ventilation maps, homogeneous krypton distribution was displayed with a gradation of red to
yellow color, while krypton defects were displayed with diminished or absent color based on
anatomical CT images. All images were evaluated by three radiologists (H.J.L, M.J.L and
S.R.H with 6, 5, and 1 years of experience in chest CT interpretation, respectively) who were
unaware of the krypton concentration, according to the following grades: Grade 1─
inhomogeneous krypton enhancement with defect area more than 50% of the entire lung;
Grade 2─ inhomogeneous krypton enhancement with defect area between 25% and 50% of
the entire lung; Grade 3─ inhomogeneous krypton enhancement with defect area less than
25% of the entire lung; and Grade 4─ uniformly homogeneous krypton enhancement in the
entire lung. Axial, coronal, and sagittal images of krypton ventilation maps were used to
visually assess each krypton concentration.
Statistical analysis
Statistical analysis was performed using software SPSS version 17 (SPSS, Inc., Chicago, IL,
USA) and SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). Quantitative variables were
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expressed as mean ± standard deviation. A linear mixed model was used to evaluate the
correlations between the CT numbers of conventional CT images and krypton concentrations
for each kVp. A linear mixed model was used to evaluate the correlation between mean
overlay HU values on krypton ventilation maps and krypton concentrations. The coefficient
of variation (equal to the standard deviation divided by the mean) was calculated to evaluate
the variation in overlay HU values on krypton ventilation maps for each krypton
concentration. We used the intraclass correlation coefficient (ICC) (0-0.20, poor; 0.21-0.40,
fair; 0.41-0.60, moderate; 0.61-0.80, good; and 0.81-1.00, excellent agreement) to evaluate
consistency between the differences in CT numbers from baseline DECT to kryptonenhanced ventilation CT at weighted average 120kVp and overlay HU values on krypton
maps. P <0.05 indicated a significant difference.
Results
During the experiments, all animals showed normal oxygen saturation of the peripheral
capillary blood from 96% to 98% on pulse oximetry. Deep anesthesia was maintained with no
spontaneous respiration.
Observers did not find any motion artifacts on any of the conventional CT images. No
animals showed abnormal lesions in the lung parenchyma on conventional CT images.
Mean CT numbers (HU) of conventional CT images according to krypton concentration
were as follows: base, -862.0 ± 38.8, -867.5 ± 38.6, and -864.5 ± 37.8; 20% krypton, -850.2 ±
37.2, -862.6 ± 39.9, and -857.9 ± 38.3; 30% krypton, -844.4 ± 35.6, -860.7 ± 34.4, and -854.1
± 35.3; 40% krypton, -838.6 ± 34.7, -858.1 ± 34.4, and -850.7 ± 33.6; 50% krypton, -832.7 ±
34.5, -855.7 ± 34.4, and -846.8 ± 32.9; 60% krypton, -828.2 ± 32.8, -853.6 ± 31.3, and -843.5
± 31.9; and 70% krypton, -822.0 ± 34.5, -850.7 ± 33.7, and -839.7 ± 32.7 (for 80kVp,
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140kVp, and weighted average 120kVp, respectively). We observed increases in CT number
as the krypton concentration increased in each kVp (Figure 2), and a linear mixed model
showed a significant correlation between CT number and krypton concentration for 80kVp,
140kVp, and weighted average 120kVp images (all P < 0.001, respectively).
Mean overlay values (HU) of krypton ventilation maps according to krypton concentration
were shown in Table 1. We also observed an increase in overlay HU value as krypton
concentration increased (Figure 3), and a linear mixed model showed a significant correlation
between overlay HU value and krypton concentration (P < 0.001). Coefficients of variation
of overlay HU values were 306.5% for 20% krypton, 159.0% for 30% krypton, 79.6% for
40% krypton, 47.5% for 50% krypton, 29.1% for 60% krypton, and 19.3% for 70% krypton.
We observed a decrease in the coefficient of variation of overlay HU values as krypton
concentration increased (Figure 3).
The agreements in terms of consistency between overlay HU values on krypton maps and
the difference between CT numbers from baseline DECT to krypton-enhanced ventilation CT
at weighted average 120kVp for each krypton concentration are summarized in Table 1.
Overall, overlay HU values were smaller than the difference of CT numbers on conventional
CT data sets, irrespective of krypton concentration. We observed moderate agreement for
20%, 30%, 40%, and 50% krypton and good agreement for 60% and 70% krypton.
The results of visual assessment are shown in Table 2. For 20% krypton, all observers
determined inhomogeneous krypton enhancement with a krypton defect area greater than
50% of the entire lung (Grade 1) in all animals. For 30% to 60% krypton, observers showed
discordance in determining the grade of krypton enhancement even in the same animals;
however, we observed a tendency of increased grade with increased krypton concentration.
All observers found homogeneous enhancement without krypton defects (Grade 4) in all
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animals for 70% krypton (Figure 4).
Discussion
In an experimental study with normal animals, we demonstrated that it is feasible to assess
pulmonary ventilation using DECT after krypton inhalation with krypton concentration of at
least 70%. As krypton concentration increased, we observed increases in CT numbers of the
lung parenchyma, especially on 80kVp images. We also found that krypton distribution in the
lungs following krypton inhalation can be extracted and displayed as a color map using the
DECT technique; however, inhalation with 20% to 60% krypton can produce ventilation
defects on krypton ventilation maps even in normal lung parenchyma.
For overlay HU values on krypton ventilation maps, we observed an increase in the value of
the normal lung parenchyma as krypton concentration increased. Coefficients of variation of
overlay HU values decreased as krypton concentration increased. Although all ROIs were
drawn in normal lung parenchyma, there were considerable variations in overlay HU values
that were obtained with lower krypton concentrations, with even negative values being
observed. Therefore, krypton extraction through software might be imperfect with lower
krypton concentrations, and these results corresponded with the heterogeneity or
homogeneity of krypton maps. In addition, we observed that overall overlay HU values on
krypton maps were smaller than the difference between CT numbers on conventional CT data
sets, irrespective of krypton concentration. This effect may be caused by partial volume
effects with air that were larger after application of filtering before material decomposition
[16]. We also observed good agreement in terms of consistency between the overlay values
on krypton maps and the difference in CT numbers on conventional CT data sets for 60% and
70% krypton concentrations. Therefore, a mixture concentration with greater than 70%
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krypton is thought to be necessary to allow regional lung ventilation evaluation with the
DECT technique.
Xenon gas was used to investigate lung ventilation with single- and dual-source dual energy
CT techniques in previous studies;[1-4,9,11] however, xenon is moderately soluble in blood
and tissue, which results in anesthetic or narcotic side effects. Therefore, concentrations of
xenon should be limited to values less than 35% [13]. Even in 30% xenon, several reports
have shown a varying proportion of patients describing transient side effects.[4,7,10] Krypton,
another radio-opaque inert gas, has a lower attenuation effect than xenon gas, but may be
useful for detecting functional alterations in the lungs with DECT because krypton has fewer
effects on the body than xenon. To overcome these limitations of xenon, one report showed
that a krypton and xenon gas mixture was a better contrast medium than a limited
concentration of xenon gas in single energy CT [17]. Another report showed that ventilation
DECT with aerosol inhalation of iodinated contrast instead of xenon in animals is feasible,
but that the safety of inhaling an iodine contrast medium is unknown [18]. In the only
relevant report that we know of, the feasibility of krypton ventilation CT using the DE
technique was shown in patients with severe chronic pulmonary disease [14]. That study used
an 80% krypton concentration to obtain the highest level of attenuation in the normal lung
because the atomic number of krypton is smaller than that of xenon, resulting in lower
attenuation. The level of enhancement was enough to differentiate between normal and
diseased lungs in that study. Even more promising, patients showed a good clinical tolerance
of krypton despite having severe chronic pulmonary disease. Despite these findings, because
the study was based on patients with severe chronic pulmonary disease, it remains uncertain
whether the normal lung parenchyma they observed was truly normal. Also, in a previous
study [13], 12 rabbits and three humans inhaled 80% krypton while showing no unequivocal
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signs of anesthetic or narcotic effects, however human subjects reported changes in voice
quality, a sensation of wanting to breathe more deeply, and an ill-defined discomfort as
adverse effects. Therefore, in this study, we aimed to assess the feasibility of kryptonenhanced ventilation CT using the DE technique in normal animals. We examined the degree
of normal lung enhancement with gradual increases in krypton concentration and sought to
determine the appropriate krypton concentration required for ventilation CT instead of an
80% concentration. As a result, we showed that a 70% krypton concentration could be
appropriate for ventilation imaging through the DE technique. Further studies with a 70%
krypton concentration are necessary for confirmation in humans.
Our study had several limitations. First, we used rabbits, which are small compared to
humans, but the tidal volume, which is the amount of air that passes in and out of the lungs
during normal breathing, is proportional to body weight (6-8ml/kg) [15]. Thus, we believe
that the 70% concentration could be applied to humans. In addition, in this study a
mechanical ventilator was used to make the delivery of krypton more effective. Further
studies are necessary to see if a 70% krypton concentration is appropriate for human patients
using a ventilator mask. Third, we obtained static CT images after three minutes of krypton
inhalation. Further dynamic studies to determine the shortest appropriate inhalation time
needed to differentiate normal and diseased lung are necessary. Fourth, although we studied
animals without spontaneous respiration under deep anesthesia and each CT scan for the
different krypton concentrations was performed during the inspiratory plateau, some
anatomical differences could still be permissible when measuring CT numbers between
conventional CT images of different krypton concentrations
In conclusion, inert krypton is feasible for use in ventilation CT with the DE technique, and
lower concentrations of krypton can create pseudo-ventilation defects on the ventilation map
13
of CT, hence 70% might be the most appropriate krypton concentration. Krypton might be a
useful alternative to xenon for ventilation CT with the DE technique. We expect future
developments in the DE technique to reduce the krypton concentrations required for
ventilation CT imaging.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
Y.E.C.: Study design, Data acquisition, Data analysis and interpretation, Manuscript
preparation, Manuscript editing
S.R.H.: Study design, Data acquisition, Data analysis and interpretation, Manuscript
preparation, Manuscript editing
M.J.L.: Study design, Quality control of data and algorithms, Data analysis and interpretation,
Manuscript review
M.S.L.: Study design, Data acquisition, Quality control of data and algorithms, Manuscript
review
Y.J.K.: Study concepts, Quality control of data and algorithms, Statistical analysis,
Manuscript review
J.H.: Study concepts, Quality control of data and algorithms, Statistical analysis, Manuscript
review
Y.J.H.: Study concepts, Quality control of data and algorithms, Statistical analysis,
Manuscript review
B.W.C.: Study concepts, Quality control of data and algorithms, Statistical analysis,
Manuscript review
H.J.L.: Study concepts, Study design, Data acquisition, Data analysis and interpretation,
Statistical analysis, Manuscript preparation, Manuscript editing,
All authors read and approved the final manuscript.
14
Acknowledgments
This study was supported by a National Research Foundation of Korea Grant funded by the
Korean government (2011-0014220).
15
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Figure Legends
Figure 1 Three coronal images for the measurement of CT number.
First, (A) on axial images, (B) one coronal image was reformatted in accordance with the
plane across the midline of carina. Next, (C,D) two coronal images were reformatted 1-cm
anterior and d posterior to the plane.
Figure 2 Mean CT number according to each krypton concentration at each kVp.
Increases in mean CT number with increases in krypton concentration for 80kVp, 140kVp,
and weighted average 120kVp were observed.
Figure 3 Overlay values on krypton maps.
As krypton concentration increased, we observed overall overlay values increasing and the
distribution of values narrowing. Note negative values seen at the lower krypton
concentrations.
Figure 4 Krypton ventilation maps with a coronal plane for each krypton concentration.
In this animal, all observers determined Grade 1 for the 20% krypton ventilation map, Grade
2 for the 30% and 40% krypton ventilation maps, Grade 3 for the 50% and 60% krypton
ventilation maps, and Grade 4 for the 70% krypton ventilation map.
19
Tables
Table 1 The results of agreement between overlay HU values and differences of CT
numbers.
Kr concentration
Overlay values (HU)*
CT number Differences (HU)†
ICC (95% CI)
20%
1.68 ± 5.15
6.65 ± 7.32
0.580 (0.338, 0.750)
30%
3.73 ± 5.93
10.44 ± 12.11
0.439 (0.159, 0.654)
40%
6.92 ± 5.51
13.84 ± 14.84
0.560 (0.312, 0.737)
50%
10.88 ± 5.17
17.73 ± 14.24
0.550 (0.299, 0.730)
60%
14.54 ± 4.23
21.03 ± 11.48
0.607 (0.374, 0.768)
70%
18.79 ± 3.63
24.85 ± 9.42
0.796 (0.651, 0.885)
Values are means ± standard deviation
Kr krypton, ICC intraclass correlation coefficient, CI confidence interval
*Overlay values on krypton maps.
†CT number differences from baseline DECT to krypton-enhanced ventilation CT at weighted average 120kVp
for each krypton concentration.
20
Table 2 The results of visual assessment of krypton ventilation color maps.
Krypton concentration
Observer 1
Observer 2
Observer 3
20%
30%
40%
50%
60%
70%
Grade 1
7
5
3
1
0
0
Grade 2
0
2
3
3
1
0
Grade 3
0
0
1
3
4
0
Grade 4
0
0
0
0
2
7
Grade 1
7
5
3
0
0
0
Grade 2
0
2
2
3
0
0
Grade 3
0
0
2
4
4
0
Grade 4
0
0
0
0
3
7
Grade 1
7
6
4
1
0
0
Grade 2
0
1
2
3
1
0
Grade 3
0
0
1
3
3
0
Grade 4
0
0
0
0
3
7
Data indicate the number of animal.
Grade 1, inhomogeneous krypton enhancement with defect area more than 50% of the entire
lung; Grade 2, inhomogeneous krypton enhancement with defect area between 25% and 50%
of the entire lung; Grade 3, inhomogeneous krypton enhancement with defect area less than
25% of the entire lung; and Grade 4, uniformly homogeneous krypton enhancement in the
entire lung.
21
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1
Figure 2
Figure 3
Figure 4